This application describes a set of experiments which we believe will provide some solid basic science underpinnings for a future in vivo gene therapy trial for Parkinson's Disease. The experiments described are not sufficient per se for a definitive preclinical assessment of these potential gene therapy reagents, however in combination with a number of toxicity/tolerance and non-human primate studies should provide some of the critical efficacy and safety data necessary for obtaining an IND. We propose using the 6-OHDA lesioned rat as experimental models. We propose using recombinant adeno-associated virus (AAV). This vector system is one in which both our understanding of the biology and the vectorology has significantly advanced in the past 4 years since we first published its potential application for CNS gene transfer. This includes analysis of its rapid and efficient infection of neurons, integration, as well as improved packaging and purification leading to higher and purer titers. Moreover, several independent investigators have also made advances in understanding which regulatory elements are necessary to both increase expression and maintain stable expression in neurons. Our focus is on the human tyrosine hydroxylase (TH) gene. This is therefore a palliative or symptomatic approach, one whose primary goal is to restore the characteristic dopamine deficit in the striatum. Although on the surface this would appear to break little new ground, there are a number of significant novel components to this study which we believe warrant serious consideration for funding: 1) Further refinements in vectorology with high titer, highly purified vector stocks; 2) Vastly improved expression cassettes; 3) Preliminary data suggesting transduction of TH alone is sufficient for complete phenotypic correction in a dopamine-deficit model; 4) Recent reports on a neuroregenerative effect of dopamimetic therapy in partial lesioned models; 5) Potential for autoregulation of the transgene based on ambient dopaminergic tone in the striatum. Therefore, the successful completion of the proposed experiments will not only bring the reality of a clinical trial for Parkinson's Disease significantly closer but should provide data to support our contention that the application of an in vivo gene transfer technology to Parkinson's Disease will be a major advance in the clinical treatment of this debilitating disease.